Microvascular disease may account for the synergistic increase in incidence of cardiac events observed during exposure to the common cardiovascular risk factors hypercholesterolemia (HC) and hypertension (HT) in the absence of significant coronary artery stenosis (CAS). However, the mechanisms underlying these effects have not been fully elucidated, because microvessels (mu-v) (<500 pm) are difficult to resolve with conventional techniques. The hypothesis underlying this proposal is that HC and HT synergistically impair myocardial mu-v function and architecture, interfere with adaptive responses, and exacerbate functional consequences of CAS for the myocardium. Furthermore, that sophisticated computed tomography (CT) and mu-v modeling methods would be useful to resolve the function and structure of myocardial mu-v and explore the effects of concurrent HC and HT. These hypotheses will be tested in a unique pig model of concurrent diet-induced HC and renovascular HT, using novel CT imaging techniques. Electron beam CT (EBCT) will be used to quantify noninvasively myocardial perfusion, transmural distribution, size-specific mu-v volume fraction, function, and permeability in response to increased cardiac demand, acute CAS, or chronic CAS. The function of small (<150 mu-m) and large (150-500 mu-m) mu-v will be studied both in vivo and in isolated vessels in vitro. Furthermore, micro-CT will be used to visualize the myocardial muv in situ and study their 3D branching and architecture, which may modulate myocardial adaptation to CAS. Chronic antioxidant intervention will be used to assess the role of increased oxidative stress as an underlying mechanism in the cross talk between HC and HT. Furthermore, the imaging studies will be correlated with in vitro studies of myocardial tissue redox status, vascular endothelial function, and growth-factor activity. These studies could greatly advance our understanding of the deleterious interaction between HC and HT, and contribute towards development of imaging strategies for physiologic assessment of the evolution and mechanisms of early atherosclerosis.